Targeted therapy of cancer typically focuses on agents that suppress oncogenic signaling below a minimum threshold needed for survival and proliferation. Here, we propose a novel strategy to overcome drug-resistance in B cell malignancies based on targeted activation of an autoimmunity checkpoint (AIC) for removal of autoreactive B cells. Owing to the necessity of the B cell repertoire to censor autoreactive clones, B cells fundamentally differ in their signaling requirements from other cell types. Unlike other types of cancer, B cell malignancies are uniquely susceptible to clonal deletion induced by hyperactive signaling from an autoreactive B cell receptor (BCR). Three recent studies from our group showed that targeted AIC-activation is achievable by pharmacological hyperactivation of BCR-signaling above a maximum threshold (Chen et al., Nature 2015; Shojaee et al., Cancer Cell 2015; Shojaee et al., Nature Med 2016). Hence, targeted AIC-activation can be leveraged for eradication of drug-resistant B cell leukemia and lymphoma clones. Based on these and other findings, we propose three Aims to validate targeted autoimmunity checkpoint (AIC)- activation as new concept for the treatment of human B cell malignancies: 1. This proposal includes a mechanistic Aim based on the novel observation that checkpoints to safeguard from autoimmunity disease are still functional in B cell malignancies. This Aim explores how AIC-activation can be reliably achieved in B cell malignancies and how AIC-activation leads to cell death. 2. The stratification Aim will identify disease subtypes and groups of patients that may be most responsive to AIC-activation and elucidate the biological basis of different treatment responses. 3. A therapeutic Aim will refine the treatment concept by prioritizing targeted hyperactivation of specific components of the BCR pathway and by exploring combinations with established treatment agents.